The long-range goals of this Program-Project Proposal are to (i) define the functional phenotypes of the uterus and the cellular changes that account for the differences in these phenotypes during pregnancy/parturition; (ii) evaluate the mechanisms by which the transitions in the uterine phenotypes is effected at the cellular/gene level; (iii) define the ontogeny/regulation of interstitial collagen formation in amnion and the impact of selected risk factors for pre-term pre-mature rupture of the fetal membranes (PT-PROM) on pro-collagen synthesis/processing; and (iv) define the cellular interactions in the fetal membranes that contribute to the tensile strength of this tissue and to liability for PT-PROM. The research is based upon several propositions as follows: (1) The spontaneous initiation of human parturition is the result of retreat from continued pregnancy maintenance, non the accelerated formation of a uterotonin; (2) the actions of progesterone are only one of several mechanisms by which uterine quiescence is maintained during the first 90-95% of pregnancy; (3) a multi-component fail-safe system that is replete with redundant processes is operative to maintain myometrial quiescence; (4) a change in uterine functional phenotype, which precedes the onset of labor, corresponds to the initiation of parturition; (5) this phenotypic change in myometrial function negates the effect of the multiple components of the fail-safe system of pregnancy maintenance; (6) this phenotypic change, involving multiple systems, may be effected by a single mechanism; (7) the function of the fetal membranes and, in particular, the amnion to establish and maintain tensile strength can be, but heretofore has not been, defined at the cellular and biomolecular level; (8) morphological/functional modifications of the lower pole of the fetal membranes that normally accompany pregnancy predispose this area of the amnion to rupture during labor, but also predispose this tissue to premature rupture when other factors mitigate against optimum interstitial collagen formation in this tissue; and, (9) pregnancies with previous episodes of PT-PROM and those of women who smoke cigarettes provide an opportunity for explorations of the factors that contribute to PT-PROM. The studies described in the 4 research projects and laboratory core are closely integrated and coordinated to achieve the long-range goals of this Program-Project proposal.